In humans, hair and skin color is related to individual factors (ethnic origin, sex, age, etc.) and environmental factors (in particular the seasons of the year, region inhabited, etc.). It is primarily determined by the nature and concentration of melanin produced by the melanocytes. The melanocytes are large dendritic cells located in the basal layer of the epidermis. These specialized cells will, by way of specific organites, the melanosomes, synthesize melanin. The synthesis of melanin or melanogenesis is a complex process of which the precise mechanisms are not yet understood, and which schematically involves the following steps:
Tyrosine→Dopa→Dopaquinone→Dopachrome→Melanin.
This melanin plays a fundamental role in the determination of skin color. We often hear of epidermal (or elementary) melanization units that correspond in fact to functional groups in which the melanocytes maintain contact with a certain number of neighboring keratinocytes, to which they transfer the pigment grains. The number of units varies according to the body region. These units contain, on average, 1 melanocyte for 36 keratinocytes (although there are variations). The transfer of pigment from the melanocyte to the keratinocytes occurs in 4 main steps:
1: synthesis of the melanosomes in the melanocyte;
2: melanization of the melanosomes in the melanocyte;
3: transfer of the melanosomes to the keratinocytes;
4: degradation and elimination of melanosomes in the keratinocytes.
As the melanin is synthesized in the melanosomes, they move from the perinuclear region to the end of the dendrites of the melanocytes. By phagocytosis, the end of the dendrites is captured by the keratinocytes, the membranes are degraded and the melanosomes are redistributed in the keratinocytes. Once in the keratinocytes, the melanosomes are distributed according to their size: in isolation for the largest ones, in groups for the smallest ones (Ortonne, et al. 1981). They are secondarily degraded in lysosomal vacuoles (Fitzpatrick et al. 1979).
The transfer of melanosomes to the keratinocytes, as described above, is performed by means of numerous biological, enzymatic processes, and is not currently fully understood. One of the players in this melanosome transfer process is SCF protein and its c-Kit receptor. The SCF (Stem Cell Factor) protein is the natural agonist ligand of the c-Kit receptor, which is a member of the sub-family III of the superfamily of receptor tyrosine kinases (RTK). It has been demonstrated in numerous publications that this SCF/c-Kit signaling pathway played a key role in a number of biological processes, and in particular in hematopoiesis, spermatogenesis, as well as in the maintenance of homeostasis of the skin and in the pigmentation of same (Longley J. et al, J Invest Dermatol. 1999; 113: 139-140).
It is known that anomalies in the transfer of melanosomes to the keratinocytes can lead to pigmentation disorders, whether of the hyperpigmentation or the hypopigmentation type. More specifically, certain studies have shown that the SCF/c-Kit signaling pathway could regulate both the proliferation and the differentiation of melanocytes. The SCF protein at the surface of the epidermal keratinocytes could enable regulation of the adjacent melanocytes, via direct interaction with the c-Kit receptor located on said melanocytes. Moreover, it has been demonstrated that certain transcription factors crucial for the synthesis of melanin were activated by the SCF/c-Kit pathway (Grichnik, J M et al. J Invest Dermatol. 1998; 111: 233-238). It can therefore be considered that the SCF/c-Kit pathway is important for the normal function of melanocytes, and that it is possible for alterations at the level of this signaling pathway are responsible for certain melanocyte disorders, i.e. pigmentation disorders.
Once within keratinocytes, melanosomes are gradually distributed to the perinuclear area. Then melanosomes densely aggregate above the nucleus in a supranuclear cap called “microparasol” in suprabasal keratinocytes. This positioning of melanosomes above the nucleus serves as a protective mechanism shielding the keratinocyte nucleus from harmful ULTRAVIOLET radiations. Both the transfer of melanosomes from melanocytes to keratinocytes and the distribution of melanosomes into microparasols are processes dependent on the movement of these organelles along microtubules. Such movements of melanosomes involve the molecular motor proteins kinesin and dynein. Cytoplasmic dynein is a multisubunit complex consisting of two heavy chains and several intermediate/light and light chains. The heavy chains contain sites for microtubule binding and ATP hydrolysis whereas the remaining subunits may contain recognition binding sites for organelles. Dynein associates with its cargoes through a complex called “dynactin complex” (Byers H R, Maheshwary S, Amodeo D M & Dystra S G. Role of cytoplasmic dynein in perinuclear aggregation of phagocytosed melanosomes and supranuclear melanin cap formation in human keratinocytes. J Invest Dermatol (2003) 121: 813-820).
In keratinocytes, dynactin p150Glued subunit acts as a “dynein anchor” and plays a role in the capture and centripetal transport of melanosomes to the perinuclear area of keratinocytes. Moreover, this protein is involved in the formation and maintenance of microparasols. Furthermore, major damages of microparasol structural and functional integrity have been observed after knockdown of p150Glued by siRNA (Alexia Lebleu et al. Maintenance of keratinocytes “microparasol” by targeting p150glued dynactin subunit, IFSCC Conference 2013. Book of Abstracts; 061:150-152).
Along with SCF/c-Kit signaling pathway, the integrity of microparasols is essential to prevent DNA photodamage of cutaneous cells.